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Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1−/− mice are viable, fertile and show no altered hematopoietic compartment. In CD4+ T cell- and dextran sodium sulfate-induced models of colitis, Trem1−/− mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1−/− mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1−/− mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1−/− mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1+/+ controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.

Adipose tissue eosinophils (ATE) are important for the control of obesity-associated inflammation and metabolic disease. However, how aging impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo significant age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment

M E hlullc7r Institute AbstractThe purpose of this study was to investigate factors which enhanced the compressive properties of alginatekhondrocyte constructs. Firstly, we studied the effect of biochemical composition (high, mid and low guluronic acid content) and sterilization method on alginate properties. Secondly, we studied the biosynthetic characteristics of chondrocytes in three different alginate compositions and performed mechanical tests to determine whether the synthesis of cartilage matrix components could significantly enhance the compressive properties. 2% alginate solutions containing an initial cell density of 4 Y lo6 cells/ml were cast into cylinders and cultured for seven weeks. Compression tests, biochemistry, immunohistochemistry and electron microscopy were performed at fixed intervals during the seven-week culture period. The dynamic modulus, peak strain, and peak stress were maximum for alginate with the highest guluronic acid content. The presence of cells and their respective matrix components enhanced the equilibrium modulus of the constructs for all types of alginate, though this effect was small. Alginate containing the middle amount of guluronic acid resulted in constructs which were both mechanically stable and which promoted synthesis of cartilage matrix proteins. In experiments and applications in which the mechanical integrity of the alginate is important, the composition and purity of the alginate and its method of sterilization should be selected with care.